The hu-HIV/PBL-SCID model was employed to explore the immunologic and virologic effects of different immune-based and antiviral therapies on the course of HIV-1 infection and disease. It was also used as a model to dissect the immunologic aspects of the human immune response to HIV, particularly in patients with stable disease. This model involves direct reconstitution of 8- to 12-week-old SCID mice with PBL from HIV-infected donors. Engraftment was achieved in 84% of mice as confirmed by both PCR detection of human cells and by detection of human antibody production and caused no diminution in the number of human mononuclear cells harvested by peritoneal lavage relative to control mice engrafted with uninfected cells. The human antibody produced by hu-HIV/PBL-SCID mice had broad reactivity against HIV. Virus was detected in 98% of mice by PCR or virus co-culture. Viremia was first detected by quantitative PCR on day 7 and persisted through day 17. Proviral DNA nucleotide sequences from peritoneal lavage cells recovered from hu-HIV/PBL-SCID mice on day 17 were not significantly changed from those derived from donor PBL at the time of injection. Reconstituted hu-HIV/PBL-SCID mice that were untreated sustained a 75% decrease in human CD4+ T-lymphocytes recovered in peritoneal wash relative to control mice, whereas treatment with the nucleoside analogue FddA both significantly reduced CD4+ cell depletion as well as diminished detectable virus. Boosting circulating human Ig antibody levels through injection of purified antibody derived from the donor's plasma with neutralizing activity did not affect the frequency of CD4+ lymphocyte recovery or virus detection. The administration of a monoclonal antibody to human tumor necrosis factor-alpha at 10mg/kg resulted in only a modest increase in the CD4+ T-lymphocyte survival. Higher doses were less effective. Studies were initiated to dissect the nature of the protective inmmune response in long term non-progressors and to examine the role of IL-12 as a therapeutic intervention.